DDS Research, Global Formulation Research Japan, Pharmaceutical Science and Technology Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
DDS Research, Global Formulation Research Japan, Pharmaceutical Science and Technology Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
J Control Release. 2015 Dec 28;220(Pt A):44-50. doi: 10.1016/j.jconrel.2015.10.024. Epub 2015 Oct 19.
Considerable efforts have been directed towards discovering and developing delivery vehicles for RNA therapeutics. While most studies emphasize the efficacy and safety of these delivery vehicles, few reports conduct a comprehensive assessment of their storage stability, a critical property for practical applications. Here, we report a potent and safe lipid nanoparticle with long-term storage stability. Through chemical synthesis and screening of cationic lipids, a formulation has been identified that enables potent knockdown of hepatocyte proteins in mice upon intravenous administration (siRNA ED50 ~0.02 mg/kg). Toxicity studies revealed that a dose of 2mg/kg was well tolerated in rats, the most sensitive rodent model. We identified that a cyclic chemical structure in cationic lipids improved particle stability. The nanoparticles showed over 1.5 year storage stability as a liquid, with over 90% siRNA encapsulation without any changes in particle size. This novel delivery material has promising potential as a drug product that could bring RNA therapeutics to the treatment of liver-related disorders.
人们已经投入了相当大的努力来发现和开发用于 RNA 治疗的递药载体。尽管大多数研究都强调了这些递药载体的功效和安全性，但很少有报告对其储存稳定性进行全面评估，而储存稳定性对于实际应用来说是至关重要的。在这里，我们报告了一种具有长期储存稳定性的强效且安全的脂质纳米颗粒。通过阳离子脂质的化学合成和筛选，我们确定了一种制剂，该制剂能够在静脉给药时（siRNA ED50~0.02mg/kg）有效降低小鼠肝细胞蛋白的水平。毒性研究表明，在最敏感的啮齿动物模型大鼠中，2mg/kg 的剂量是可以耐受的。我们发现阳离子脂质中的环状化学结构可以提高颗粒的稳定性。该纳米颗粒在液体状态下具有超过 1.5 年的储存稳定性，siRNA 包裹率超过 90%，而粒径没有任何变化。这种新型递药材料具有作为药物产品的巨大潜力，可以将 RNA 治疗应用于治疗肝脏相关疾病。
